Aporphine alkaloids are present in more than 100 plants from more than 20 families and are important secondary metabolites of plants. This type of compounds typically has significant pharmacological activities, such as anti-oxidation, anti-platelet-aggregation, anti-convulsion, anti-spasm, anti-malaria, anti-protozoa, anti-poliovirus, cytotoxicity, anti-Parkinson's disease, and the like. Isocorydine is a typical aporphine alkaloid, and is widely distributed in plants, such as Dicranostigma leptopodum (see ZL201310107231.8), Dactylicapnos scandens, Stephania epigaea, Corydalis yanhusuo, Nandina domestica, Stephania brachyandra, Coptis chinensis, Bergenia purpurascens, and the like.
It has been indicated by researches that isocorydine can remarkably reduce the proportion of CD133+ positive or EpCAM labeled tumor stem cells and can significantly reduce the spherization and the clonogenicity of CD133+ cells. It has been revealed by researches in vivo that isocorydine may reduce the tumorigenicity of CD133+, isocorydine may significantly reduce the proportion of side population cells in hepatocellular carcinoma cell (HCC) lines, and significantly downregulate the expression of a drug-resistant protein ABCG2 in a dose-dependent manner. It has been demonstrated by tumor xenograft models that isocorydine can selectively reduce the volume and the weight of a tumor induced by side population cells in vivo. It has been indicated by combinated therapy that isocorydine may enhance the drug sensitivity of HCC strains to doxorubicin and plays a role in the reversion of drug resistance. It has been indicated by researches that isocorydine has an activity of targeting HCC side population cells and HCC stem cells and has an activity of reversing drug resistance and is a very potential chemotherapeutic drug for treating hepatocellular carcinoma. (Sun H F, Hou H L, Lu P, et al. Isocorydine inhibits cell proliferation in hepatocellular carcinoma cell cines by inducing G2/M cell cycle arrest and apoptosis. PLoS ONE, 2012, 7(5): e36808; Lu P, Sun H F, Zhang L X, et al. Isocorydine targets the drug-resistant cellular side population through PDCD4-related apoptosis in hepatocellular carcinoma. Mol Med, 2012, 18(7): 1136-1146.). However, isocorydine has a limited inhibition activity for tumor growth of various HCC, and IC50 values are all greater than 200 μM. Therefore, with respect to 8-amino-isocorydine (named as NICD in this patent application, see ZL 201210340250.0), which is obtained by performing chemical structure derivation and anti-cancer activity screening researches by the applicant of the patent, the anti-cancer activity is greatly improved. It has been indicated by researches that NICD may selectively act on key targets of tumor cells such as IGF2BP3, GADD45A, and the like and tumor stem cells labeled with CD133+ and may downregulate the expression of drug-resistant drug pump proteins ABCG2 and ABCB1 at the same time, has multi-drug resistance reversion effect and synergistic effect with sorafenib, and has the prospect of new drug development. The applicant of the patent has established relationships between multi-drug resistance of tumor, tumor stem cells, and metastasis and invasion of tumor by the targeted intervention of NICD for the first time, making it possible to solve three core problems in the treatment of hepatocellular carcinoma by one drug. (Chen L J, Tian H, Li M, et al. Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis, Tumour Biol, 2016, 37: 5951-5961; Li M, Zhang L X, Ge C, et al, An isocorydine derivative (d-ICD) inhibits drug resistance by downregulating IGF2BP3 expression in hepatocellular carcinoma. Oncotarget, 2015, 6(28): 25149-25160.). However, in view of the objective presence of the chemical structure fragment of p-aminophenol in the chemical structure of NICD, it results in that NICD cannot be stored in an aqueous solution for a long period, otherwise it will be easily oxidized and degraded and there is a defect in stability. Additionally, compared to modern targeted anti-cancer drugs, it is possible to further optimize its anti-cancer activity.
Sorafenib (having a structural formula as shown in FIG. 1) is the only multi-target tyrosine kinase inhibitor which has been successfully marketed hitherto, is used for treating hepatocellular carcinoma in late stages in which standard therapies are ineffective or cannot be tolerant, and is a gold standard for the treatment of hepatocellular carcinoma in late stages. Although sorafenib may effectively elongate the overall survival time of an HCC patient (by 2 months), toxic and side effects of drugs, drug resistance, and the like generated after administration will severely influence the quality of life and therapeutic effects. Additionally, its high cost is not affordable for most patients. Compound 35 (having a structural formula as shown in FIG. 1) may be used as a type II inhibitor of a tyrosine kinase receptor protein c-KIT kinase and may effectively inhibit the c-KIT kinase and a T670I mutant of c-KIT, and shows a strong anti-proliferation effect for GISTs cancer cell lines GIST-T1 and GIST-5R. (Li B H, Wang A L, Liu J, et al. Discovery of N ((1-(4-(3-(3-((6,7-Dimethoxyquinolin-3-yl)oxy)phenyl)ureido)-2-(trifluoromethyl)phenyl)piperidin-4-1)methyl) propionamide (CHMFL-KIT-8140) as a highly potent type II inhibitor capable of inhibiting the T670I “Gatekeeper” mutant of cKIT kinase. J Med Chem, 2016, 59(18): 8456-8472.). Olaparib (having a structural formula with reference to FIG. 1) is a selective PARP1/2 inhibitor and is used for treating tumors in which BRCA is mutated, for example, ovarian cancer, thymic cancer, and prostate cancer. Additionally, olaparib has selectivies in inhibiting tumor cells having ATM defects, indicating that olaparib may be used as a potential drug for treating lymphomas in which ATM is mutated.

In light of modern drug design concepts and computer-aided drug design and using molecular docking simulation and optimization, the applicant of the patent has found that when an amino group is introduced at the position C-8 of isocorydine and then chemical structure optimization is further performed on the amino group at C-8, a series of compounds having anti-cancer activities are designed with reference to pharmacophore models of sorafenib, compound 35, and olaparib. The anti-cancer activities of chemical structure derivatives of isocorydine may be significantly improved.